Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex steroid responsible for the development and regulation of the female reproductive system and secondary sex characteristics.
There are three major endogenous estrogens that have estrogenic hormonal activity:
estrone (E1),
estradiol (E2), and
estriol (E3).
[ Another estrogen called estetrol (E4) is produced only during pregnancy.
]
Estrogens are synthesized in all vertebrates
Like all , estrogens readily diffusion across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the gene expression of many .
Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs),
In addition to their role as natural hormones, estrogens are used as , for instance in menopausal hormone therapy, hormonal birth control and feminizing hormone therapy for Trans woman, intersex people, and nonbinary people.
Synthetic and natural estrogens have been found in the environment and are referred to as . Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) and can cause health issues and reproductive dysfunction in both wildlife and humans.
(1998). 058515807X, Marcel Dekker. 058515807X
Types and examples
The four major naturally occurring estrogens in women are
estrone (E1),
estradiol (E2),
estriol (E3), and
estetrol (E4). Estradiol (E2) is the predominant estrogen during reproductive years both in terms of absolute serum levels as well as in terms of estrogenic activity. During
menopause, estrone is the predominant circulating estrogen and during pregnancy estriol is the predominant circulating estrogen in terms of serum levels. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.
Thus, estradiol is the most important estrogen in non-pregnant females who are between the
menarche and menopause stages of life. However, during
pregnancy this role shifts to estriol, and in postmenopausal women estrone becomes the primary form of estrogen in the body. Another type of estrogen called
estetrol (E4) is produced only during pregnancy. All of the different forms of estrogen are synthesized from
, specifically
testosterone and
androstenedione, by the
enzyme aromatase.
Minor endogenous estrogens, the biosyntheses of which do not involve aromatase, include 27-hydroxycholesterol, dehydroepiandrosterone (DHEA), 7-oxo-DHEA, 7α-hydroxy-DHEA, 16α-hydroxy-DHEA, 7β-hydroxyepiandrosterone, androstenedione (A4), androstenediol (A5), 3α-androstanediol, and 3β-androstanediol.
Biological function
The actions of estrogen are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls
gene expression. Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor. The estrogen:ER complex binds to specific DNA sequences called a hormone response element to activate the transcription of target genes (in a study using an estrogen-dependent breast cancer cell line as model, 89 such genes were identified).
Since estrogen enters all cells, its actions are dependent on the presence of the ER in the cell. The ER is expressed in specific tissues including the ovary, uterus and breast. The metabolic effects of estrogen in postmenopausal women have been linked to the genetic polymorphism of the ER.
While estrogens are present in both man and woman, they are usually present at significantly higher levels in biological females of reproductive age. They promote the development of female secondary sexual characteristics, such as breasts, darkening and enlargement of nipples,
and thickening of the
endometrium and other aspects of regulating the menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of
sperm and may be necessary for a healthy
libido.
Overview of actions
-
Musculoskeletal
-
Anabolic: Increases muscle mass and strength, speed of muscle regeneration, and bone density, increased sensitivity to exercise, protection against muscle damage, stronger collagen synthesis, increases the collagen content of connective tissues, , and , but also decreases stiffness of and (especially during menstruation). Decreased stiffness of tendons gives women much lower predisposition to muscle strains but soft ligaments are much more prone to injuries (ACL tears are 2-8x more common among women than men).
-
Reduce bone resorption, increase bone formation
-
In mice, estrogen has been shown to increase the proportion of the fastest-twitch (type IIX) muscle fibers by over 40%.
[ "Supplementation with estrogen increases the type-IIX percentage composition in the plantaris back to 42%. (70)"]
-
Metabolic
-
Anti-inflammatory properties
-
Accelerate metabolism
-
Gynoid fat distribution: increased fat distribution or estrogenic fat in some body parts such as breasts, buttocks, and legs but decreased abdominal and visceral fat (androgenic obesity).
-
Estradiol also regulates energy expenditure, body weight homeostasis, and seems to have much stronger anti-obesity effects than testosterone in general.
-
Other structural
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Maintenance of vessels and skin
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Protein synthesis
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Increase hepatic production of
-
Increase production of the hepatokine adropin.
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Coagulation
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Lipid
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Fluid balance
-
Salt (sodium) and water retention, including facial swelling and edema
-
Estrogen is associated with edema, including facial and abdominal swelling.
-
Melanin
-
Estrogen is known to cause darkening of skin, especially in the face and areolae.
[ "The results of this study suggest that there are indeed sex-specific genetic effects in human pigmentation, with larger effects for darker pigmentation in females compared to males. A plausible cause might be the differentially expressed melanogenic genes in females due to higher oestrogen levels. These sex-specific genetic effects would help explain the presence of darker eye and skin pigmentation in females, as well as the well-known higher melanoma risk displayed by males."]
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Lung function
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Promotes lung function by supporting alveoli (in rodents but probably in humans).
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Sexual
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Mediate formation of female secondary sex characteristics
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Stimulate endometrium growth
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Increase uterus growth
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Increase vaginal lubrication
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Thicken the wall
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Uterus lining
-
Estrogen together with progesterone promotes and maintains the uterus lining in preparation for implantation of fertilized egg and maintenance of uterus function during gestation period, also upregulates oxytocin receptor in myometrium
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Ovulation
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Surge in estrogen level induces the release of luteinizing hormone, which then triggers ovulation by releasing the egg from the Graafian follicle in the ovary.
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Sexual behavior
-
Estrogen is required for female mammals to engage in lordosis behavior during estrus (when animals are "in heat").
-
Sex drive is dependent on androgen levels
Female pubertal development
Estrogens are responsible for the development of female secondary sexual characteristics during
puberty, including breast development, widening of the
, and female
fat distribution. Conversely,
are responsible for
pubic hair and
body hair hair growth, as well as
acne and
body odor.
Breast development
Estrogen, in conjunction with
growth hormone (GH) and its secretory product insulin-like growth factor 1 (IGF-1), is critical in mediating breast development during
puberty, as well as breast maturation during
pregnancy in preparation of
lactation and
breastfeeding.
Estrogen is primarily and directly responsible for inducing the ductal component of breast development,
as well as for causing
fat deposition and connective tissue growth.
[ It is also indirectly involved in the lobuloalveolar component, by increasing progesterone receptor expression in the breasts]
such as testosterone powerfully oppose estrogen action in the breasts, such as by reducing estrogen receptor expression in them.
Female reproductive system
Estrogens are responsible for maturation and maintenance of the vagina and uterus, and are also involved in ovary function, such as maturation of . In addition, estrogens play an important role in regulation of gonadotropin secretion. For these reasons, estrogens are required for female fertility.
Neuroprotection and DNA repair
Estrogen regulated DNA repair mechanisms in the brain have neuroprotective effects.
Brain and behavior
Sex drive
Estrogens are involved in libido (sex drive) in both women and men.
Cognition
Verbal memory scores are frequently used as one measure of higher level cognition. These scores vary in direct proportion to estrogen levels throughout the menstrual cycle, pregnancy, and menopause. Furthermore, estrogens when administered shortly after natural or surgical menopause prevents decreases in verbal memory. In contrast, estrogens have little effect on verbal memory if first administered years after menopause.
The protective effects of estrogens on cognition may be mediated by estrogen's anti-inflammatory effects in the brain.
Mental health
Estrogen is considered to play a significant role in women's mental health. Sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained low estrogen levels correlate with a significant lowering of mood. Clinical recovery from postnatal, perimenopause, and postmenopause depression has been shown to be effective after levels of estrogen were stabilized and/or restored.
Compulsions in male lab mice, such as those in obsessive-compulsive disorder (OCD), may be caused by low estrogen levels. When estrogen levels were raised through the increased activity of the enzyme aromatase in male lab mice, OCD rituals were dramatically decreased. Hypothalamus protein levels in the gene COMT are enhanced by increasing estrogen levels which are believed to return mice that displayed OCD rituals to normal activity. Aromatase deficiency is ultimately suspected which is involved in the synthesis of estrogen in humans and has therapeutic implications in humans having obsessive-compulsive disorder.
Local application of estrogen in the rat hippocampus has been shown to inhibit the re-uptake of serotonin. Contrarily, local application of estrogen has been shown to block the ability of fluvoxamine to slow serotonin clearance, suggesting that the same pathways which are involved in SSRI efficacy may also be affected by components of local estrogen signaling pathways.
Parenthood
Studies have also found that fathers had lower levels of cortisol and testosterone but higher levels of estrogen (estradiol) than did non-fathers.
Binge eating
Estrogen may play a role in suppressing binge eating. Hormone replacement therapy using estrogen may be a possible treatment for binge eating behaviors in females. Estrogen replacement has been shown to suppress binge eating behaviors in female mice.[
]
It is also suggested that there is an interaction between hormone levels and eating at different points in the female menstrual cycle. Research has predicted increased emotional eating during hormonal flux, which is characterized by high progesterone and estradiol levels that occur during the mid-luteal phase. It is hypothesized that these changes occur due to brain changes across the menstrual cycle that are likely a genomic effect of hormones. These effects produce menstrual cycle changes, which result in hormone release leading to behavioral changes, notably binge and emotional eating. These occur especially prominently among women who are genetically vulnerable to binge eating phenotypes.
Binge eating is associated with decreased estradiol and increased progesterone.[ Progesterone may moderate the effects of low estradiol (such as during dysregulated eating behavior), but that this may only be true in women who have had clinically diagnosed binge episodes (BEs). Dysregulated eating is more strongly associated with such ovarian hormones in women with BEs than in women without BEs.]
The implantation of 17β-estradiol pellets in ovariectomized mice significantly reduced binge eating behaviors and injections of GLP-1 in ovariectomized mice decreased binge-eating behaviors.[
]
The associations between binge eating, menstrual-cycle phase and ovarian hormones correlated.
Masculinization in rodents
In rodents, estrogens (which are locally aromatized from androgens in the brain) play an important role in psychosexual differentiation, for example, by masculinizing territorial behavior;
Skeletal system
Estrogens are responsible for both the pubertal growth spurt, which causes an acceleration in linear growth, and epiphyseal closure, which limits human height and limb length, in both females and males. In addition, estrogens are responsible for bone maturation and maintenance of bone mineral density throughout life. Due to hypoestrogenism, the risk of osteoporosis increases during menopause.
Cardiovascular system
Women are less impacted by heart disease due to vasculo-protective action of estrogen which helps in preventing atherosclerosis.[
]
Immune system
The effect of estrogen on the immune system is in general described as Th2 favoring, rather than suppressive, as is the case of the effect of male sex hormone – testosterone.[ Estrogen also influences by increasing their survival, proliferation, differentiation and function, which corresponds with higher antibody and B cell count generally detected in women.]
On a molecular level estrogen induces the above-mentioned effects on cell via acting on intracellular receptors termed ER α and ER β, which upon ligation form either homo or heterodimers. The genetic and nongenetic targets of the receptors differ between homo and heterodimers.[ A non-transcriptional response to oestrogen stimulation was also documented (termed membrane-initiated steroid signalling, MISS). This pathway stimulates the ERK and PI3K/AKT pathways, which are known to increase cellular proliferation and affect chromatin remodelation.][
]
Associated conditions
Researchers have implicated estrogens in various estrogen-dependent conditions, such as ER-positive breast cancer, as well as a number of genetic conditions involving estrogen signaling or metabolism, such as estrogen insensitivity syndrome, aromatase deficiency, and aromatase excess syndrome.
High estrogen can amplify stress hormone responses in stressful situations.[
]
Biochemistry
Biosynthesis
Estrogens, in females, are produced primarily by the ovary, and during pregnancy, the placenta.[ and the level of aromatase.]
In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of weak androgenic activity which serves predominantly as a precursor for more potent androgens such as testosterone as well as estrogen. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted either immediately into estrone, or into testosterone and then estradiol in an additional step. The conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion of androstenedione and testosterone into estrone and estradiol, respectively is catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase, whereas theca cells express these enzymes and 17β-HSD but lack aromatase. Hence, both granulosa and theca cells are essential for the production of estrogen in the ovaries.
Estrogen levels vary through the menstrual cycle, with levels highest near the end of the follicular phase just before ovulation.
Note that in males, estrogen is also produced by the when FSH binds to their FSH receptors.
Distribution
Estrogens are plasma protein bound to albumin and/or sex hormone-binding globulin in the circulation.
Metabolism
Estrogens are metabolism via hydroxylation by cytochrome P450 such as CYP1A1 and CYP3A4 and via conjugation by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). In addition, estradiol is dehydrogenation by 17β-hydroxysteroid dehydrogenase into the much less potent estrogen estrone. These reactions occur primarily in the liver, but also in other tissues.
Excretion
Estrogens are inactivated primarily by the and liver and excreted via the gastrointestinal tract
Medical use
Estrogens are used as , mainly in hormonal contraception, hormone replacement therapy,
Chemistry
The estrogen steroid hormones are estrane steroids.
History
In 1929, Adolf Butenandt and Edward Adelbert Doisy independently isolated and purified estrone, the first estrogen to be discovered.
The word estrogen derives from Ancient Greek. It is derived from "oestros"[ It was first published in the early 1920s and referenced as "oestrin".]
Society and culture
Etymology
The name estrogen is derived from the Greek language οἶστρος (), literally meaning "verve" or "inspiration" but figuratively sexual passion or desire,
Environment
A range of synthetic and natural substances that possess estrogenic activity have been identified in the environment and are referred to .
Estrogens are among the wide range of endocrine-disrupting compounds (EDCs) because they have high estrogenic potency. When an EDC makes its way into the environment, it may cause male reproductive dysfunction to wildlife and humans.[ The estrogen excreted from farm animals makes its way into fresh water systems.]
Cosmetics
Some hair on the market include estrogens and placental extracts; others contain . In 1998, there were case reports of four prepubescent African-American girls developing breasts after exposure to these shampoos.
In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.[
]
See also
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List of steroid abbreviations
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Breastfeeding and fertility
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Vasoprotective
External links
